Administration of hydrophobic drugs presents practical challenges due to the limited water solubility of this class of pharmaceuticals. Accordingly, a primary focus of drug delivery research is development of effective approaches for the formulation and controlled delivery for this class of important pharmaceutical agents. Nanoemulsions are a particularly promising delivery vehicle for these applications given their intrinsic stability and potential to access useful pharmacokinetic properties for drug administration, absorption and targeting.
Nanoemulsions are composed of nanoscale droplets of one immiscible liquid dispersed within another. In the context of many pharmaceutical applications, for example, the dispersed droplet phase of a nanoemulsion provides a central oil core, stably dispersed in an aqueous phase, that can act as an effective reservoir for hydrophobic drugs. Nanomemulsions for delivery applications often incorporate one or more surfactants and/or stabilizers to facilitate stabilization and improve drug solubilization of the dispersed phase. As nonequilibrium systems, preparation of a nanoemulsion typically involves an input of energy, for example, using a microfluidiser, high pressure homogeniser or ultrasonicator.
Typical droplet sizes for nanoemulsions for the delivery of pharmaceuticals are in the range of about 20-500 nm. The small droplet size characteristic of nanoemulsions provides benefits supporting their use as vehicles for pharmaceutical delivery. First, the small droplet size and lower surface tension between dispersed and aqueous phases decrease the rates of droplet agglomeration and precipitation processes so as to substantially limit the potential for phase separation via sedimentation, flocculation, coalescence and creaming. As a result, nanoemulsions are typically more kinetically stable than other types of emulsions. Second, the nanosized dimensions of the droplets allow for effective in vivo administration, for example via drug absorption from the gastrointestinal tract or penetration of the skin barrier. Third, the large interfacial area provided by the small size of the dispersed droplets allows for the potential to effectively control drug release over a clinically useful range. Accordingly, nanoemulsions have significant potential for providing rapid, sustained or targeted delivery and release of hydrophobic drugs.
While emulsions have long been used for topical administration, recent research has been directed to development of emulsion-based delivery systems effective for parenteral, inhalation and oral delivery. Phospholipid-stabilized soybean oil emulsions were the first approved intravenous emulsion and have been used clinically as i.v. nutritional supplements for over 40 years. More recently, however, emulsions have been developed and employed widely in the clinic for the delivery of certain hydrophobic drugs, such as anesthetics, anti-inflammatory and analgesic drugs, and also as blood substitutes.
Commercial propofol (i.e., Diprivan), for example, consists of an Intralipid® emulsion of the active agent 2,6-diisopropylphenol. The lipid emulsion-based formulation of propofol is used extensively for anesthesiology practices for inducing and maintaining general anesthesia. In addition, this emulsion-based formulation of propofol is used for procedural sedation and sedation in intensive care settings. Current lipid emulsion-based formulations of propofol are susceptible to problems relating to the ability of their lipid component (e.g. soybean oil) to support bacterial and fungal growth. To address the risk of contamination, for example, tubing and open vials of propofol must be replaced every twelve hours for many clinical applications. In addition, infusion at high rates or as large bolus can result in lipid intolerance, which may contribute to propofol infusion syndrome, a rare but serious complication that further limits use of lipid-based emulsions of propofol in intensive care settings.
It will be appreciated from the foregoing that emulsion-based delivery systems for the formulation and administration of hydrophobic drugs are needed. Systems and formulations are needed that are capable of providing stable formulation of hydrophobic drugs exhibiting sparing solubility in aqueous solutions, particularly, in concentrations supporting a range of important clinical applications. Systems and formulations are needed exhibiting a high degree of biocompatibility, low toxicity and pharmacokinetic properties supporting controlled delivery and targeting of hydrophobic drugs.